Metal-free C-N- and N-N-bond formation: Synthesis of 1,2,3-triazoles from ketones, N-tosylhydrazines, and amines in one pot

Article abstract of DOI:10.1002/chem.201405057

A novel synthetic approach toward 1,4-disubstitut-ed 1,2,3-triazoles by C-N- and N-N-bond formation has been established under transition-metal-free conditions. Complete control of the regioselectivity was successfully achieved. Commercially available ani

Full text of DOI:10.1002/chem.201405057

DOI: 10.1002/chem.201405057
Full Paper
&
Nitrogen Heterocycles
Metal-Free CÀN- and NÀN-Bond Formation: Synthesis of 1,2,3-
Triazoles from Ketones, N-Tosylhydrazines, and Amines in One Pot
Zhengkai Chen,[a] Qiangqiang Yan,[a] Zhanxiang Liu,[a] and Yuhong Zhang*[a, b]
Abstract: A novel synthetic approach toward 1,4-disubstitut-
ed 1,2,3-triazoles by CÀN- and NÀN-bond formation has
been established under transition-metal-free conditions.
Complete control of the regioselectivity was successfully
achieved. Commercially available anilines, ketones, and
N-tosylhydrazine were treated with molecular iodine in one
pot to allow the regioselective generation of 1,4-disubstitut-
ed 1,2,3-triazoles in high yields without the use of azides.
Introduction
copper salt must be applied. Considering the wide application
of 1,2,3-triazoles in pharmaceutical and life sciences research,
the development of metal-free methodology is highly desira-
ble to avoid possible metal contamination of the heterocyclic
products; trace residues of copper may spoil further property
investigation in many cases. However, achievement of the pre-
cise synthesis of 1,2,3-triazoles without the use of metals is
a significant challenge. It is known that the spontaneous regio-
selective formation of CÀN and NÀN bonds is quite difficult
without the help of transition metals.[9] Recently, a metal-free
method for the synthesis of 1,2,3-triazoles by condensation of
a,a-dichlorotosylhydrazones with primary amines was reported
by Westermann and co-workers.[10] This method has aroused
much attention and has been used broadly for the construc-
tion of 1,2,3-triazoles, although the preparation and handling
of a,a-dichlorotosylhydrazones is not convenient.[11] Herein, we
report a metal-free, mild, operationally simple, and practical
approach to access to 1,4-disubstituted 1,2,3-triazoles from ani-
lines 1, ketones 2, and N-tosylhydrazine (3) in one pot
(Scheme 1). More significantly, complete regiocontrol was ach-
1,2,3-Triazoles are key structural moieties in functional materi-
als, bioactive products, and pharmaceutical agents.[1] Therefore,
the development of chemical methods that allow the selective
construction of this five-membered heterocyclic framework is
an important research field in organic synthesis. In 1963, Huis-
gen and co-workers explored the synthesis of triazoles by un-
catalyzed thermally induced dipolar cycloaddition of alkynes
with organic azides.[2] The disadvantages of the Huisgen-type
reaction include the limited substrate scope and low regiose-
lectivity. Later, the groups of Sharpless[3] and Meldal[4] estab-
lished the copper-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction, which remarkably increases the reaction rate
and regioselectivity of the 1,4-disubstituted triazole isomer.
The CuAAC reaction has had a huge impact on organic synthe-
sis as a premier example of click chemistry and has been
widely utilized, both in industry and academia.[5] Other metal
catalysts[6] and organocatalysts[7] have also been investigated
for the synthesis of 1,2,3-triazoles.
However, all of the above methods involve the use of
sodium azides or organic azides, which are toxic and difficult
to handle, especially on a large scale. Recently, we reported
a copper-mediated method for the synthesis of 1,2,3-triazoles
from N-tosylhydrazones and amines, which provides an alter-
native route to access of 1,2,3-triazoles without the use of
azides.[8] Although the efficiency and regioselectivity of our re-
cently developed procedure is good, a significant amount of
Scheme 1. Metal-free approach to 1,2,3-triazoles.
[a] Z. Chen, Q. Yan, Z. Liu, Prof. Dr. Y. Zhang
ZJU-NHU United R&D Center
ieved for the spontaneous formation of CÀN and NÀN bonds
by the choice of easy-to-handle and inexpensive molecular
iodine as the activator. Control experiments were performed to
gain insight into the nature of this new reaction.
Department of Chemistry, Zhejiang University
Hangzhou 310027 (P. R. China)
E-mail: yhzhang@zju.edu.cn
[b] Prof. Dr. Y. Zhang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405057.
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2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), N-fluoro-
benzenesulfonimide (NFSI), benzoquinone (BQ), and PhI(OAc)2,
had a detrimental effect on the reaction (Table 1, entries 17–
20). Oxone and K2S2O8 promoted the reaction, but afforded
lower yields (Table 1, entries 21–22). The reaction gave a 45%
yield under an oxygen atmosphere (Table 1, entry 23). Because
TBHP is expensive and difficult to handle on a large scale, the
optimal reaction conditions were determined as: iodine
(1.5 equiv), DMSO, 1008C, 12 h. The reaction promoted by 1 or
1.5 equivalents of iodine under a nitrogen atmosphere was
conducted (Table 1, entry 24 and 25). The efficiency of the re-
action is related to the amount of iodine under an inert atmos-
phere: the use of iodine (1 equiv) gave 48% of 5b, whereas
iodine (1.5 equiv) afforded a higher yield of 64%. These results
indicate that oxygen is involved in the reaction as an oxidant.
With the newly developed metal-free protocol, a variety of
arylketones 2 were subjected to the optimized conditions
(Table 2). The results are especially remarkable when compared
to the synthesis of 1,2,3-triazoles from N-tosylhydrazones and
amines, reported previously by us,[8] in which N-tosylhydra-
zones with electron-withdrawing substituents on the aryl ring
showed very low reactivity and N-tosylhydrazones with sub-
stituents such as trifluoromethyl on the aryl ring failed to give
the corresponding triazoles. To our delight, the metal-free
system displayed good tolerance towards a range of electron-
withdrawing groups, including ÀCF3, ÀNO2, and ÀCOOH, to
give the corresponding triazoles in good yields (4a–g, 46–
87%). However, the aryl ketones that bore electron-donating
groups still showed better reactivity and gave higher yields
(4h–n, 61–92%). Steric hindrance played little role in this trans-
formation, both ortho- and meta-substituted aryl ketones pre-
sented excellent reactivity (4h–j, 74–92%). A disubstituted aryl
ketone participated smoothly in the reaction to afford 4k in
85% isolated yield. 1-(Naphthalen-2-yl)ethanone worked well
in this transformation to smoothly give 4o. It should be noted
that the heterocycle-substituted triazoles 4p–t could be ob-
tained in moderate-to-good yields from the corresponding het-
erocyclic ketones (39–79%). However, extension of the reaction
to aryl, alkyl ketone precursors with a longer alkyl chain, such
as aryl propanones or 1-phenylpropan-2-one, to form 1,4,5-tri-
substituted triazoles failed.
Results and Discussion
Molecular iodine has been widely used as the activator for
a range of transformations due to its low toxicity and cost.[12]
We began our study by optimizing the amount of iodine re-
quired for the reaction (Table 1). A solution of p-toluidine (1b),
Table 1. Optimization of the reaction conditions[a]
Entry
I2 [equiv]
Additive
Solvent
Yield[b] [%]
1
2
3
4
5
0.5
1.0
1.2
1.5
2.0
3.0
–
–
–
–
–
–
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
CH3CN
1,4-dioxane
DMF
34
65
70
86
62
27
0
15
trace
10
55
trace
30[c]
76[d]
81[e]
76
0
18
trace
15
62
6
7
8
9
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.5
–
–
–
–
–
–
–
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
DCE
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
TBHP
TEMPO
NFSI
BQ
PhI(OAc)2
Oxone
K2S2O8
O2
58
45
48[f]
64[f]
–
–
[a] Reaction conditions: 1b (0.6 mmol), 2a (0.5 mmol), 3 (0.75 mmol), ad-
ditive (0.5 mmol), solvent (2 mL), 1008C, 12 h. [b] Isolated yield. [c] T=
608C. [d] T=808C. [e] T=1208C. [f] Under N2 atmosphere.
acetophenone (2a), and 3 in DMSO was treated with iodine
(0.5 equiv) at 1008C for 12 h. A clean 1,4-disubstituted isomer
4-phenyl-1-p-tolyl-1H-1,2,3-triazole (5b) was obtained in 34%
yield (Table 1, entry 1). Further studies revealed that the addi-
tion of iodine (1.5 equiv) showed the best efficiency and gave
the triazole 5b in 86% yield (Table 1, entries 2–4). Further in-
creases of the amount of iodine led to a decrease of the yield
(Table 1, entries 5 and 6). Iodine proved to be crucial to the re-
action and no reaction was observed in the absence of iodine
(Table 1, entry 7). The use of solvents other than DMSO, such
as toluene, CH3CN, 1,4-dioxane, DMF, and 1,2-dichloroethane
(DCE), resulted in lower yields (Table 1, entries 8–12). A temper-
ature screen revealed that the transformation at 1008C deliv-
ered the highest isolated yield (Table 1, entries 13–15). Interest-
ingly, a compatible yield could be obtained by the use of
iodine (50 mol%) in the presence of tert-butylhydroperoxide
(TBHP, 1.0 equiv) (Table 1, entry 16). Oxidant additives, such as
We subsequently applied this new method with a range of
anilines, as shown in Table 3. The electron-rich anilines, includ-
ing methyl, methoxyl, tert-butyl, and phenyl could be smoothly
converted to the desired triazole products in high yields
(5a–h, 79–93%). Electron-deficient anilines also showed better
reactivity relative to our previous copper-mediated system.[8]
For example, anilines that bear halogen substituents were well
tolerated and the corresponding triazole products were isolat-
ed in good yields (5i–k, 72–80%). Although the strongly elec-
tron-deficient aniline 4-aminobenzonitrile was inactive in our
copper-mediated system, the corresponding triazole 5l was
isolated under the present optimized conditions in an accepta-
ble yield (46%). Notably, strongly electron-withdrawing groups
in the meta-position exhibited good-to-excellent reactivity
(5m–n, 75–90%). Naphthalen-1-amine and isoquinolin-8-amine
participated efficiently in the reaction to give the correspond-
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Table 2. Synthesis of 1,2,3-triazoles from a variety of ketones.[a, b]
Table 3. Synthesis of 1,2,3-triazoles from diverse amines.[a,b]
[a] Reaction conditions: 1 (0.6 mmol), 2a (0.5 mmol), 3 (0.75 mmol), I2
(0.75 mmol), DMSO (2 mL), 1008C, 12 h. [b] Isolated yields. [c] I2
(0.25 mmol), TBHP (0.5 mmol, 70% in water), 1,4-dioxane (2 mL), 1008C,
12 h. [d] I2 (0.25 mmol), Oxone (0.5 mmol), 1,4-dioxane (2 mL), 1008C,
12 h.
[a] Reaction conditions: 1a (0.6 mmol), 2 (0.5 mmol), 3 (0.75 mmol), I2
(0.75 mmol), DMSO (2 mL), 1008C, 12 h. [b] Isolated yield.
ing triazoles in good yields (5o–p, 64–74%). In the case of ali-
phatic amines, a complex mixture was produced and the de-
sired triazoles were quite difficult to isolate. Gratifyingly, experi-
mentation revealed that butyl amine afforded the desired tria-
zole 5q in 67% yield when the reaction conditions were
switched to iodine (50 mol%) and TBHP (1 equiv). However,
other amines tested failed to give the corresponding triazoles
under these conditions. After further optimization of the reac-
tion conditions, we obtained alkyl-substituted triazoles 5r--t by
the combination of iodine (50 mol%) and Oxone (1 equiv),
albeit in lower yields.
Two plausible pathways are proposed (Scheme 2). Phenyl-
glyoxal intermediate A formed in the presence of iodine and
DMSO by Kornblum oxidation[13] undergoes condensation with
the aniline to form the C-acyl imine intermediate B. Subse-
quent condensation of intermediate B with N-tosylhydrazine
Scheme 2. A plausible mechanism.
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affords intermediate C, which undergoes cyclization and aro-
matization in the presence of molecular iodine or O2 to gener-
ate the triazole product (Path I). Another possible pathway is
the formation of N-tosylhydrazone D by the reaction of an aryl-
ketone with N-tosylhydrazine. Subsequent a-iodogenation of
the N-tosylhydrazone forms intermediate E. Elimination of HI
from E gives the key intermediate 1-tosyl-2-vinyldiazene F,[14]
which undergoes aza-Michael addition with the aniline to gen-
erate intermediate G. Oxidative cyclization and aromatization
of intermediate G in the presence of iodine affords the triazole
product (Path II). Direct nucleophilic attack of aniline onto in-
termediate E is another possible route for the formation of
intermediate G.
Scheme 4. Scaleup of the reaction.
by formation of a NÀN bond to afford the final triazole 5b in
the presence or absence of iodine (Scheme 3e).
We performed the reaction on a gram scale (Scheme 4) and
were pleased to find that the triazole product 5b was ob-
tained in 81% yield. This satisfactory result presents the possi-
bility for large-scale applications of this methodology.
To gain further insight into the reaction mechanism, we per-
formed the control experiments illustrated in Scheme 3. It was
found that treatment of 2a with molecular iodine and DMSO
The sulfonamide moiety is the core structure of carbonic an-
hydrase (CA) inhibitors.[15] The CA inhibitor properties can be
readily tuned with respect to structure–property and struc-
ture–activity parameters by covalently tethering a tail fragment
onto an established primary sulfonamide CA-recognition phar-
macophore, as in compound 6 (Scheme 5).[15a] By the use of
Scheme 5. Synthetic utilization of the metal-free method.
our method, the “tail approach” can be easily achieved with
high efficiency from commercially available chemicals in one
pot. This metal-free method provides straightforward access to
useful bioactive molecules.
Conclusion
A new synthetic method for the construction of CÀN and NÀN
bonds under metal-free conditions has been demonstrated.
More significantly, the transformation is operationally simple
and executed in one pot from commercially available reagents
to regioselectively afford 1,4-disubstituted 1,2,3-triazoles in
high yields under mild conditions. The substrate scope is
broad and the reaction can be readily scaled up to gram scale,
which thereby offers a practical approach for the production
of diverse 1,2,3-triazoles. Further investigations to extend the
reaction scope and elucidate the possible mechanism are in
progress.
Scheme 3. Control experiments.
first produced intermediate A, and subsequent addition of 1 f
generated C-acyl imine intermediate B (Scheme 3a). The reac-
tion of intermediate B with 3 gave the triazole product 5 f in
78% yield (Scheme 3b). The reaction of intermediate A, 1b,
and 3 in one pot also afforded the triazole product 5b in 72%
yield (Scheme 3c). These results provide evidence for Path I.
On the other hand, we prepared N-tosylhydrazone D and treat-
ed it with 1b under the standard reaction conditions
(Scheme 3d). The desired triazole product 5b was obtained in
85% yield, indicative that the triazole can also be formed by
Path II. Importantly, we found that intermediate G, which was
prepared by a literature method,[8] could be smoothly cyclized
Experimental Section
Representative procedure for the formation of 1,2,3-tri-
azoles
I2 (0.75 mmol) was added to a mixture of 1b (0.6 mmol), 2a
(0.5 mmol), and 3 (0.75 mmol) in DMSO (2 mL). The mixture was
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Eur. J. 2011, 17, 3584–3587; c) M. Belkheira, D. E. Abed, J.-M. Pons, C.
Bressy, Chem. Eur. J. 2011, 17, 12917–12921; d) L. Wang, S. Y. Peng,
L. J. T. Danence, Y. Gao, J. Wang, Chem. Eur. J. 2012, 18, 6088–6093;
e) N. Seus, L. C. Goncalves, A. M. Deobald, L. Savegnago, D. Alves, M. W.
Paixao, Tetrahedron 2012, 68, 10456–10463; f) D. K. J. Yeung, T. Gao, J.
Huang, S. Sun, H. Guo, J. Wang, Green Chem. 2013, 15, 2384–2388;
g) W. Li, Q. Jia, Z. Du, J. Wang, Chem. Commun. 2013, 49, 10187–10189;
h) D. B. Ramachary, A. B. Shashank, Chem. Eur. J. 2013, 19, 13175–
13181; i) J. Thomas, J. John, N. Parekh, W. Dehaen, Angew. Chem. Int. Ed.
2014, 53, 10155–10159; Angew. Chem. 2014, 126, 10319–10323; j) D. B.
Ramachary, A. B. Shashank, S. Karthik, Angew. Chem. Int. Ed. 2014, 53,
10420–10424; Angew. Chem. 2014, 126, 10588–10592.
stirred at 1008C under air for 4–12 h. After completion of the reac-
tion (monitored by TLC), the reaction mixture was cooled to ambi-
ent temperature and water (30 mL) was added to the mixture,
which was then extracted with EtOAc (3ꢁ50 mL). The extract was
washed with 10%w/w Na2S2O3 (aq), dried over anhydrous Na2SO4,
and the solvent was removed under vacuum to provide the crude
product, which was purified by column chromatography on silica
gel to afford 5b as a light-yellow solid (86%).
Acknowledgements
[8] a) Z. Chen, Q. Yan, Z. Liu, Y. Xu, Y. Zhang, Angew. Chem. Int. Ed. 2013, 52,
13324–13328; Angew. Chem. 2013, 125, 13566–13570; b) Z. Chen, Q.
Yan, H. Yi, Z. Liu, A. Lei, Y. Zhang, Chem. Eur. J. 2014, 20, 13692-13697.
[9] a) J. J. Neumann, M. Suri, F. Glorius, Angew. Chem. Int. Ed. 2010, 49,
7790–7794; Angew. Chem. 2010, 122, 7957–7961; b) S. Ueda, H. Naga-
sawa, J. Am. Chem. Soc. 2009, 131, 15080–15081; c) M. Suri, T. Jous-
seaume, J. J. Neumann, F. Glorius, Green Chem. 2012, 14, 2193–2196;
d) D.-G. Yu, M. Suri, F. Glorius, J. Am. Chem. Soc. 2013, 135, 8802–8805.
[10] S. S. van Berkel, S. Brauch, L. Gabriel, M. Henze, S. Stark, D. Vasilev, L. A.
Wessjohann, M. Abbas, B. Westermann, Angew. Chem. Int. Ed. 2012, 51,
5343–5346; Angew. Chem. 2012, 124, 5437–5441.
We gratefully acknowledge the Natural Science Foundation of
China (21272205), the National Basic Research Program of
China (2011CB936003), and the Program for the Zhejiang Lead-
ing Team of Science and Technology Innovation (2011R50007)
for financial support.
Keywords: anilines · ketones · metal-free reactions · synthetic
methods · 1,2,3-triazoles
[11] a) B. Fçhlisch, R. Flogaus, Synthesis 1984, 734–736; b) J. Barluenga, L.
Llavona, J. M. Concellon, M. Yus, J. Chem. Soc. Perkin Trans. 1 1991, 297–
300; c) R. Hanselmann, G. E. Job, G. Johnson, R. Lou, J. G. Martynow,
M. M. Reeve, Org. Process Res. Dev. 2010, 14, 152–158.
[1] a) H. Wamhoff, in Comprehensive Heterocyclic Chemistry, Vol. 5 (Eds.: A. R.
Katritzky, C. W. Rees), Pergamon, Oxford, 1984, pp. 669; b) S. T. Abu-
Orabi, M. A. Atfah, I. Jibril, F. M. Mari’i, A. A. Ali, J. Heterocycl. Chem.
1989, 26, 1461–1468; c) L. S. Kallander, Q. Lu, W. Chen, T. Tomaszek, G.
Yang, D. Tew, T. D. Meek, G. A. Hofmann, C. K. Schulz-Pritchard, W. W.
Smith, C. A. Janson, M. D. Ryan, G. F. Zhang, K. O. Johanson, R. B. Kirkpa-
trick, T. F. Ho, P. W. Fisher, M. R. Mattern, R. K. Johnson, M. J. Hansbury,
J. D. Winkler, K. W. Ward, D. F. Veber, S. K. Thompson, J. Med. Chem.
2005, 48, 5644–5647; d) A. Lauria, R. Delisi, F. Mingoia, A. Terenzi, A.
Martorana, G. Barone, A. M. Almerico, Eur. J. Org. Chem. 2014, 3289–
3306.
[2] a) R. Huisgen, Angew. Chem. Int. Ed. Engl. 1963, 2, 565–598; Angew.
Chem. 1963, 75, 604–637; b) R. Huisgen, Angew. Chem. Int. Ed. Engl.
1963, 2, 633–645; Angew. Chem. 1963, 75, 742–754; c) R. Huisgen, R.
Knorr, L. MÅbius, G. Szeimies, Chem. Ber. 1965, 98, 4014–4021.
[3] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem.
Int. Ed. 2002, 41, 2596–2599; Angew. Chem. 2002, 114, 2708–2711.
[4] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057–
3064.
[5] a) Click Chemistry for Biotechnology and Materials Science, (Ed.: J.
Lahann), Wiley-VCH, Weinheim, 2009; b) A. E. Speers, G. C. Adam, B. F.
Cravatt, J. Am. Chem. Soc. 2003, 125, 4686–4687; c) L. V. Lee, M. L.
Mitchell, S.-J. Huang, V. V. Fokin, K. B. Sharpless, C.-H. Wong, J. Am.
Chem. Soc. 2003, 125, 9588–9589; d) J. E. Moses, A. D. Moorhouse,
Chem. Soc. Rev. 2007, 36, 1249–1262; e) M. Meldal, C. W. Tornøe, Chem.
Rev. 2008, 108, 2952–3015; f) P. Thirumurugan, D. Matosiuk, K. Jozwiak,
Chem. Rev. 2013, 113, 4905–4979.
[6] a) J. Barluenga, C. Valdꢂs, G. Beltrꢃn, M. Escribano, F. Aznar, Angew.
Chem. Int. Ed. 2006, 45, 6893–6896; Angew. Chem. 2006, 118, 7047–
7050; b) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B. Sharp-
less, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127, 15998–15999;
c) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G.
Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130, 8923–8930; d) J. McNulty,
K. Keskar, Eur. J. Org. Chem. 2012, 5462–5470; e) M. Boominathan, N.
Pugazhenthiran, M. Nagaraj, S. Muthusubramanian, S. Murugesan, N.
Bhuvanesh, ACS Sustainable Chem. Eng. 2013, 1, 1405–1411; f) S. Ding,
G. Jia, J. Sun, Angew. Chem. Int. Ed. 2014, 53, 1877–1880; Angew. Chem.
2014, 126, 1908–1911.
[12] a) F.-L. Yang, S.-K. Tian, Angew. Chem. Int. Ed. 2013, 52, 4929–4932;
Angew. Chem. 2013, 125, 5029–5032; b) F.-L. Yang, F.-X. Wang, T.-T.
Wang, Y.-J. Wang, S.-K. Tian, Chem. Commun. 2014, 50, 2111–2113; c) S.
Tang, Y. Wu, W. Liao, R. Bai, C. Liu, A. Lei, Chem. Commun. 2014, 50,
4496–4499; d) Y. Yan, Y. Zhang, C. Feng, Z. Zha, Z. Wang, Angew. Chem.
Int. Ed. 2012, 51, 8077–8081; Angew. Chem. 2012, 124, 8201–8205; e) T.
Nobuta, N. Tada, A. Fujiya, A. Kariya, T. Miura, A. Itoh, Org. Lett. 2013, 15,
574–577; f) T. Nobuta, A. Fujiya, T. Yamaguchi, N. Tada, T. Miura, A. Itoh,
RSC Adv. 2013, 3, 10189–10192; g) W. Wei, Y. Shao, H. Hu, F. Zhang, C.
Zhang, Y. Xu, X. Wan, J. Org. Chem. 2012, 77, 7157–7165; h) Y.-P. Zhu, Z.
Fei, M.-C. Liu, F.-C. Jia, A.-X. Wu, Org. Lett. 2013, 15, 378–381; i) Q. Gao,
X. Wu, S. Liu, A. Wu, Org. Lett. 2014, 16, 1732–1735; j) X. Wu, Q. Gao, S.
Liu, A. Wu, Org. Lett. 2014, 16, 2888–2891; k) Q. Gao, S. Liu, X. Wu, A.
Wu, Org. Lett. 2014, 16, 4582–4585; l) L. Cao, J. Ding, M. Gao, Z. Wang,
J. Li, A. Wu, Org. Lett. 2009, 11, 3810–3813.
[13] a) N. Kornblum, W. J. Jones, G. J. Anderson, J. Am. Chem. Soc. 1959, 81,
4113–4114; b) N. Kornblum, J. W. Powers, G. J. Anderson, W. J. Jones,
H. O. Larson, O. Levand, W. M. Weaver, J. Am. Chem. Soc. 1957, 79,
6562–6562.
[14] a) J. M. Hatcher, D. M. Coltart, J. Am. Chem. Soc. 2010, 132, 4546–4547;
b) O. A. Attanasi, G. Favi, P. Filippone, G. Giorgi, F. Mantellini, G. Mosca-
telli, D. Spinelli, Org. Lett. 2008, 10, 1983–1986; c) O. A. Attanasi, G.
Favi, P. Filippone, F. Mantellini, D. Moscatelli, F. R. Perrulli, Org. Lett.
2010, 12, 468–471; d) J.-R. Chen, W.-R. Dong, M. Candy, F.-F. Pan, M.
Jçrres, C. Bolm, J. Am. Chem. Soc. 2012, 134, 6924–6927; e) M.-C. Tong,
X. Chen, J. Li, R. Huang, H. Tao, C.-J. Wang, Angew. Chem. Int. Ed. 2014,
53, 4680–4684; Angew. Chem. 2014, 126, 4768–4772.
[15] a) A. J. Salmon, M. L. Williams, Q. K. Wu, J. Morizzi, D. Gregg, S. A. Char-
man, D. Vullo, C. T. Supuran, S-A. Poulsen, J. Med. Chem. 2012, 55,
5506–5517; b) S.-A. Poulsen, B. L. Wilkinson, A. Innocenti, D. Vullo, C. T.
Supuran, Bioorg. Med. Chem. Lett. 2008, 18, 4624–4627; c) J. Kaur, A.
Bhardwaj, S. K. Sharma, F. Wuest, Bioorg. Med. Chem. 2013, 21, 4288–
4295; d) N. Pala, L. Micheletto, M. Sechi, M. Aggarwal, F. Carta, R.
McKenna, C. T. Supuran, ACS Med. Chem. Lett. 2014, 5, 927–930.
[7] a) D. B. Ramachary, K. Ramakumar, V. V. Narayana, Chem. Eur. J. 2008, 14,
9143–9147; b) L. J. T. Danence, Y. Gao, M. Li, Y. Huang, J. Wang, Chem.
Received: September 2, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
A novel synthetic approach toward
1,4-disubstituted 1,2,3-triazoles by CÀN-
and NÀN-bond formation has been es-
tablished under transition-metal-free
conditions (see scheme). Complete con-
trol of regioselectivity was successfully
achieved and anilines, ketones, and
N-tosylhydrazines were treated with
molecular iodine in one pot to allow
the formation of 1,4-disubstitued 1,2,3-
triazoles in high yields without the use
of azides.
&
Nitrogen Heterocycles
Z. Chen, Q. Yan, Z. Liu, Y. Zhang*
&& – &&
Metal-Free CÀN- and NÀN-Bond
Formation: Synthesis of 1,2,3-Triazoles
from Ketones, N-Tosylhydrazines, and
Amines in One Pot
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!